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Psychedelics in Psychiatry–Keeping the Renaissance From Going Off the Rails

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Abstract

There is a resurgence, some say renaissance, of clinical research on psychedelic substances after decades of dormancy. Recent studies have produced findings suggesting psychedelics may demonstrate substantial efficacy for serious psychiatric conditions such as mood and substance use disorders. As a result, ongoing clinical trials with the psychedelic psilocybin have been given the Breakthrough Therapy designation by the US Food and Drug Administration that could result in medical approval for major depressive disorder and/or treatment-resistant depression.
Psychedelics in Psychiatry—Keeping the Renaissance From
Going Off the Rails
There is a resurgence, some say renaissance, of clini-
cal research on psychedelic substances after decades of
dormancy. Recentstudies have produced findings sug-
gesting psychedelics may demonstrate substantial effi-
cacy for serious psychiatric conditions such as mood and
substance use disorders. As a result, ongoing clinical trials
with the psychedelic psilocybin have been given the
Breakthrough Therapy designation by the US Food and
Drug Administration that could result in medical ap-
proval for major depressive disorder and/ortreatment-
resistant depression.
This new period of psychedelic research, ongoing
since at least 2006, has now lasted for about the same
length of time as psychedelic research in the 1950s and
1960s did before it ground to a halt. As contemporary
psychedelic research results accrue, the field may be fac-
ing a fork in the road to clinical applications. One path
forward allows for the same kinds of exuberance, uto-
pian thinking, and uneven clinical approaches that con-
tributed to ending the previous period of research. Com-
bined with the contemporary tendency to politicize
science, the possibility of a repeat of the 1960s repre-
sents a significant concern. Another path forward, a more
careful and systematic one, involves the appropriate in-
tegration of psychedelic treatments into existing evi-
dence-based psychiatric paradigms such as psycho-
therapy and pharmacotherapy.
This Viewpoint offers perspectives on how the psy-
chedelic research renaissance can stay on the path that
leads to the integration of these medications into the
standard of care rather than recapitulating the ethical and
sociopolitical problems that led to the previous period
of research going off the rails.
History of Psychedelic Research
Psilocybin is a psychedelic compound in certain mush-
rooms, which have been used in sacred ceremonies
among indigenous peoples in Mexico and elsewhere for
centuries. Other psychedelic compounds, such as mes-
caline and DMT (N,N-dimethyltryptamine), have like-
wise been used for hundreds or thousands of years in
ritual contexts. The psychedelic LSD (lysergic acid di-
ethylamide), which the Swiss chemist Albert Hofmann
synthesized in 1938, led to innovations in understand-
ing serotonin pharmacology and, eventually (albeit in-
directly), to the development of therapeutics that modu-
late serotonin function such as selective serotonin
reuptake inhibitors.
During a period in the 1950s and 1960s, research es-
tablished that psychedelic substances produce substan-
tially altered states of consciousness. This era of re-
search showed psychedelics as having considerable
promise in the treatment of depression in patients with
cancer and alcohol use disorder. However, in the late
1960s, clinical research on psychedelics was function-
ally prohibited because of burdensome governmental
regulations, the perceived association of the sub-
stances with an anti-establishment counterculture, mis-
perception of risk resulting from negatively biased me-
dia coverage, and lapses in research ethics.
Recent Research
After several decades of inactivity in the US, psyche-
delic research in healthy psychedelic-naive partici-
pants was restarted at Johns Hopkins in 2000. Studies
have focused on the serotonergic psychedelics (espe-
cially psilocybin), so called because these compounds
function as partial 5-HT
2A
serotonin receptor agonists.
1
Many studies have confirmed the low toxicity and mini-
mal addiction potential of serotonergic and other
psychedelics.
1
The study most often cited as restarting the cur-
rent period of psychedelic research was a double-blind
randomized clinical trial that examined psilocybin ad-
ministered in a supportive setting. The intervention re-
sulted in long-term increases in positive mood, life sat-
isfaction, and prosocial behavior in healthy participants.
2
Two double-blind randomized clinical trials on patients
with life-threatening cancer diagnoses showed sus-
tained decreases in anxiety and depression.
3,4
Addi-
tional research in clinical populations has suggested ef-
ficacy for treatment of mood disorders and substance
use disorders.
5-7
These and other recent and ongoing
studies suggest the potential for psychedelics to be used
as new and effective treatments for a range of psychi-
atric conditions.
Dead Ends
Despite this promise, cultural forces such as those that
occurred in the 1960s may threaten contemporary re-
search progress and the clinical application of psyche-
delics. For example, numerous recent popular press
books, websites, podcasts, and media reports have un-
critically promoted presumed benefits of psychedelics.
Patient demand is growing, as is interest in the general
population, with the possibility that expectations are out-
pacing the current data on what outcomes can be con-
fidently foreseen. Psychedelics are neither a cure for
mental disorders nor a quick fix for an unfulfilled life and
should not be portrayed as a panacea. Ominously, pro-
psychedelic subcultures are increasingly fostering uto-
pian visions for society based on research findings that,
while intriguing, still must be considered preliminary.
If psychedelic research is going to avoid another pe-
riod of prohibition, we must learn from the lessons of the
past. It is critically important that the medical and sci-
VIEWPOINT
David B. Yaden,PhD
Department of
Psychiatry and
Behavioral Sciences,
Johns Hopkins
University School of
Medicine, Baltimore,
Maryland; and Center
for Psychedelic and
Consciousness
Research, Johns
Hopkins University
School of Medicine,
Baltimore, Maryland.
Mary E. Yaden,MD
Department of
Psychiatry,Perelman
School of Medicine,
University of
Pennsylvania,
Philadelphia.
Roland R. Griffiths,
PhD
Department of
Psychiatry and
Behavioral Sciences,
Johns Hopkins
University School of
Medicine, Baltimore,
Maryland; and Center
for Psychedelic and
Consciousness
Research, Johns
Hopkins University
School of Medicine,
Baltimore, Maryland.
Corresponding
Author: Roland R.
Griffiths, PhD,
Psychiatry,Johns
Hopkins Center for
Psychedelic and
Consciousness
Research, 5510 Nathan
Shock Dr, Baltimore,
MD 21224 (rgriff@jhmi.
edu).
Opinion
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entific communities be vigilant in opposing the conflation of sci-
ence with larger cultural agendas, as occurred in the 1960s with the
blending of psychedelics into the antiwar and other anti-
establishment movements. The enthusiasms that attend such agen-
das should not be allowed to supersede the scientific and regula-
tory processes meant to carefully vet these substances and their
application in a variety of mood and behavioral disorders.
A Way Forward
More randomized clinical trials are necessary to replicate and ex-
tend the promising findings of open-label trials and to better un-
derstand contraindications and other potential risks. Furthermore,
additional studies will be required to better understand the mecha-
nisms by which psychedelics exert their therapeutic effects, ideal
dosing schedules, selection of the most effective compounds, and
optimal clinical management. The lure of the approval of the clini-
cal use of psychedelics raises the possibility that a vast arrayof eclec-
tic and untested psychotherapeutic techniques may be applied in
conjunction with medication administration. Considering that psy-
chedelic experiences are known to be strongly influenced by expec-
tations and the context (ie, set and setting) and that such experi-
ences sometimes result in major shifts in worldview, adding
psychedelics to fringe or unproven psychotherapeutic paradigms
may increase the risk of iatrogenic harm. The safest and most effec-
tive psychedelic treatment protocols will likely be those that inte-
grate existing evidence-based interventions and psychotherapies.
Conclusions
Psychiatric treatments have seen only modest innovation for de-
cades. Research on psychedelics is pointing to the potential for new
treatment options for a variety of psychiatric conditions. However,
as testing and clinical applications expand, it is still possible for re-
searchers and clinicians to squander this opportunity.The word re-
naissance comes from the French wordfor rebir th; however, this may
be somewhat of a misnomer as it has been more than 2 decades since
clinical psychedelic research resumed in the US. We believethis new
era of psychedelic research is no longer being reborn but rather com-
ing into maturity. Whether this era of psychedelic research will con-
clude with another scientific and clinical dead-end period of prohi-
bition or move ahead into a productive time of mainstream research
and clinical application remains to be seen. We owe it to the next
generation of researchers and clinicians, and to the millions of pa-
tients with mood and substance use disorders who may benefit from
these treatments, to ensure that no exceptions be made in the stan-
dards of research or clinical application for psychedelics, regard-
less of their seemingly exceptional potential.
ARTICLE INFORMATION
Published Online: December 2, 2020.
doi:10.1001/jamapsychiatry.2020.3672
Conflict of Interest Disclosures: Dr Griffiths
reports grants from the Steven and Alexandra
Cohen Foundation and from Tim Ferris, Matt
Mullenweg, Blake Mycoskie, and Craig Nerenberg
for funding the Johns Hopkins Center for
Psychedelic and Consciousness Research (CPCR)
during the conduct of the study; grants from the
Riverstyx Foundation, a crowdsourced funding
campaign organized by Tim Ferriss, and National
Institute on Drug Abuse (grant R01DA03889) for
research support outside the submitted work;
personal fees from the Heffter Research Institute
(HRI) to cover travel costs as member of the board
of directors of HRI outside the submitted work; and
is site principal investigator for a multisite trial of
psilocybin-facilitated treatment of major depressive
disorder, which is sponsored by the Usona Institute.
No other disclosures were reported.
Funding/Support: Support for Drs D. Yadenand
Griffiths through the Johns Hopkins Center for
Psychedelic and Consciousness Research was
provided by Tim Ferriss, Matt Mullenweg, Blake
Mycoskie, Craig Nerenberg, and the Steven and
Alexandra Cohen Foundation. Dr M. Yaden was
supported by the National Institute of Mental
Health (grant R25MH119043).
Role of the Funder/Sponsor:The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We thank James B.
Potash, MD (Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University
School of Medicine), for his helpful comments and
suggestions. He was not compensated.
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Opinion Viewpoint
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Background: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Methods: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. Findings: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. Interpretation: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. Funding: Medical Research Council.
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